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Award Ceremony Speech

Presentation Speech by Professor G.
Liljestrand, member of the Staff of Professors of the Royal Caroline Institute,
on December 10, 1945

Your Majesties, Your Royal Highnesses,
Ladies and Gentlemen.

Attempts have been made to reach the goal of medical art - the
prevention and cure of disease - by many different paths. New and
reliable ones have become practicable as our knowledge of the
nature of the different diseases has widened. Thus the successful
combating of certain disturbances in the activities of the organs
of internal secretion, as also of the deficiency diseases, or
avitaminoses, has been a direct result of the increase in our
knowledge of the nature of these afflictions. When, thanks to the
research work of Louis Pasteur and Robert Koch, the nature of the
infectious diseases was laid bare, and the connection between
them and the invasion of the body by bacteria and other
micro-organisms was elucidated, fully a generation ago, this was
an enormous advance, both for the prevention and the treatment of
this important group of diseases. This was so much the more
important as the group included a number of the worst scourges of
humanity, which had slain whole peoples, and at times had laid
waste wide areas. But now possibilities were revealed which have
not yet been by any means fully utilized. In rapid succession,
different forms of vaccination were evolved, and subsequently
also serum treatment, for the introduction of which the first Nobel Prize for Physiology or
Medicine was given 44 years ago today. In these cases
advantage was taken of the capacity of the human and animal
bodies themselves to produce protective substances in the fight
against the invaders, and to do so in great abundance. But it is
by no means the higher organisms only that are able to produce
such substances. In cooperation with Joubert (1877), Pasteur
himself observed that anthrax bacilli cultivated outside the body
were destroyed if bacteria from the air were admitted, and with
prophetic acumen he realized that it was justifiable to attach
great hopes to this observation in the treatment of infectious
diseases. Nevertheless more than two decades passed before an
attempt was made to profit by the struggle for existence which
goes on between different species of micro-organisms. Experiments
carried out by Emmerich and Loew (1899) did not give such
favourable results, however, that any great interest was aroused,
nor did success attend the later efforts of Gratia and Dath and
others. It was reserved to this year's Nobel Prize winners to
realize Pasteur's idea.

The observation made by Professor Alexander Fleming which led to
the discovery of penicillin, is now almost classical. In 1928, in
the course of experiments with pyogenic bacteria of the
staphylococcus group, he noticed that, around a spot of mould
which had chanced to contaminate one of his cultures, the
colonies of bacteria had been killed and had dissolved away.
Fleming had earlier made a study of different substances which
prevent the growth of bacteria and, inter alia, had come
upon one in lacrimal fluid and saliva, the so-called lysozyme. As
he points out himself, he was therefore always on the look-out
for fresh substances which checked bacteria, and he became
sufficiently interested in his latest find to make a closer
investigation of the phenomenon. The mould was therefore
cultivated and subsequently transferred to broth, where it grew
on the surface in the form of a felted green mass. When the
latter was filtered off a week later, it was found that the broth
had such a strongly checking effect on bacteria that even when
diluted 500-800 times it completely prevented the growth of
staphylococci; consequently an extremely active substance had
passed to the broth from the mould. This proved to belong to the
Penicillium group or brush moulds, and therefore first the
broth, and later the substance itself, was called
«penicillin». It was soon realized that most of the
species of Penicillium did not form it at all, and a
closer scrutiny showed that the species which polluted Fleming's
culture was Penicillium notatum. It had been described for
the first time by Richard Westling, in the thesis which he
defended in the autumn of 1911 at the University of Stockholm for the
degree of Doctor of Philosophy - an illustration of the
international nature of science, but also of the suddenly
increased importance which sometimes accrues to sound work as a
result of further developments. Fleming also showed that
penicillin was extremely effective against cultures of many
different kinds of bacteria, above all against those belonging to
the coccus group, among them those that usually give rise to
suppuration, pneumonia and cerebral meningitis, but also against
certain other types, such as diphtheria, anthrax, and gas
gangrene bacteria. But as numerous other species, among them the
influenza, coli, typhoid and tuberculosis bacilli, grew even if
they were exposed to moderate quantities of penicillin, Fleming
was able to work out a method for isolating out from a mixture of
bacteria those which were insensitive to penicillin. He found,
further, that the white blood corpuscles, which are usually so
sensitive, were not affected by penicillin. When injected into
mice, too, it was fairly harmless. In this respect penicillin
differs decisively from other substances which had been produced
earlier from micro-organisms, and which were certainly found to
be noxious to bacteria, but at the same time at least equally
noxious to the cells of the higher animals. The possibility that
penicillin might be used as a remedy was therefore within reach,
and Fleming tested its effect on infected wounds, in some cases
with moderate success.

Three years after Fleming's discovery, the English biochemists
Clutterbuck, Lovell, and Raistrick, endeavoured to obtain
penicillin in the pure form, but without success. They
established, inter alia, that it was a sensitive substance
which easily lost its antibacterial effect during the purifying
process, and this was soon confirmed in other quarters.

Penicillin would undoubtedly still have remained a fairly unknown
substance, interesting to the bacteriologist but of no great
practical importance, if it had not been taken up at the
Pathological Institute at the venerable University of Oxford. This time a
start was again made from what is usually called basic research.
Professor Howard Florey, who devoted his attention to the body's
own natural protective powers against infectious diseases,
together with his co-workers, had studied the lysozyme referred
to above, the nature of which they succeeded in elucidating. Dr.
Ernst Boris Chain, a chemist, took part in the final stage of
these investigations, and during 1938 the two researchers jointly
decided to investigate other antibacterial substances which are
formed by micro-organisms, and in that connection they
fortunately thought first of penicillin. It was certainly obvious
that the preparation of the substance in a pure form must involve
great difficulties, but on the other hand its powerful effect
against many bacteria gave some promise of success. The work was
planned by Chain and Florey, who, however, owing to the vastness
of the task, associated with themselves a number of enthusiastic
co-workers, among whom mention should be made especially of
Abraham, Fletcher, Gardner, Heatley, Jennings, Orr-Ewing, Sanders
and Lady Florey. Heatley worked out a convenient method of
determining the relative strength of a fluid with a penicillin
content, by means of a comparison under standard conditions of
its antibacterial effect with that of a penicillin solution
prepared at the laboratory. The amount of penicillin found in one
cc. of the latter was called an Oxford unit.

In the purifying experiments then made, the mould was cultivated
in a special nutritive fluid in vessels, to which air could only
gain access after it had been filtered through cotton wool. After
about a week the penicillin content reached its highest value,
and extraction followed. In this connection advantage was taken
of the observation that the free penicillin is an acid which is
more easily dissolved in certain organic solvents than in water,
while its salts with alkali are more readily dissolved in water.
The culture fluid was therefore shaken with acidified ether or
amyl acetate. As, however, the penicillin was easily broken up in
water solution, the operation was performed at a low temperature.
Thus the penicillin could be returned to the water solution after
the degree of acidity had been reduced to almost neutral
reaction. In this way numerous impurities could be removed, and
after the solution had been evaporated at a low temperature it
was possible to obtain a stable dry preparation. The strength of
this was up to 40-50 units per mg and it prevented the growth of
staphylococci in a dilution of at least 1 per 1 million - thus
the active substance had been successfully concentrated very
considerably. It was therefore quite reasonable that it was
thought that almost pure penicillin had been obtained - in a
similar manner, in their work with strongly biologically active
substances, many earlier researchers had thought that they were
near to producing the pure substance. The further experiments,
which were made subsequently with the help of the magnificent
resources of modern biochemistry proved, however, that such was
not the case. In reality the preparation just mentioned contained
only a small percentage of penicillin. Now when it has become
possible to produce pure penicillin in a crystalline form, it has
been found that one mg contains about 1,650 Oxford units. It is
also known that penicillin is met with in some different forms,
which possibly have somewhat different effects. The chemical
composition of penicillin has also been elucidated in recent
years, and in this work Chain and Abraham have successfully taken
part.

The Oxford school was able to confirm Fleming's observation that
penicillin was only slightly toxic, and they found that its
effect was not weakened to any extent worth mentioning in the
presence of blood or pus. It is readily destroyed in the
digestive apparatus, but after injection under the skin or into
the muscles, it is quickly absorbed into the body, to be rapidly
excreted again by way of the kidneys. If it is to have an effect
on sick persons or animals, it should therefore be supplied
uninterruptedly or by means of closely repeated injections - some
more recent experiments indicate that gradually perhaps it will
be possible to overcome the difficulties in connection with
taking the preparation by mouth. Experiments on mice infected
with large doses of pyogenic or gas gangrene bacteria, which are
sensitive to penicillin, proved convincingly that it had a
favourable effect. While over 90% of the animals treated with
penicillin recovered, all the untreated control animals
died.

Experiments on animals play an immense role for modern medicine;
indeed it would certainly be catastrophic if we ventured to test
remedies on healthy or sick persons, without having first
convinced ourselves by experiments on animals that the toxic
effect is not too great, and that at the same time there is
reason to anticipate a beneficial result. Tests on human beings
may, however, involve many disappointments, even if the results
of experiments on animals appear to be clear. At first this
seemed to be the case with penicillin, in that the preparation
gave rise to fever. Fortunately this was only due to an impurity,
and with better preparations it has subsequently been possible to
avoid this unpleasant effect.

The first experiments in which penicillin was given to sick
persons were published in August 1941 and appeared promising, but
owing to the insufficient supplies of the drug, the treatment in
some cases had to be discontinued prematurely. However, Florey
succeeded in arousing the interest of the authorities in the
United States in the new substance, and with the cooperation of
numerous research workers it was soon possible, by means of
intensive work, to obtain materially improved results there and
to carry on the preparation in pure form to the crystallization
stage just mentioned. Large quantities of penicillin could be
made available, and numerous tests were made above all in the
field, but to a certain extent also in the treatment of
civilians. Many cases were reported of patients who had been
considered doomed or had suffered from illness for a long period
without improvement, although all the resources of modern
medicine had been tried, but in which the penicillin treatment
had led to recoveries which not infrequently seemed miraculous.
Naturally such testimony from experienced doctors must not be
underestimated, but on the other hand we must bear in mind the
great difficulties in judging the course of a disease.
«Experience is deceptive, judgment difficult», is one
of Hippocrates' famous aphorisms. Therefore it is important that
a remedy should be tested on a large material and in such a way
that comparison can be made with cases which have not been given
the remedy but had otherwise received exactly the same treatment.
There are now many reports of such investigations. The
extraordinarily good effects of penicillin have been established
in a number of important infectious illnesses, such as general
blood poisoning, cerebral meningitis, gas gangrene, pneumonia,
syphilis, gonorrhea and many others. It is of special importance
that even sick persons who are not favourably affected by the
modern sulfa drugs are not infrequently cured with penicillin.
The effect naturally depends on the remedy being given in a
suitable manner and in sufficient doses. On the other hand,
experience has confirmed what might have been surmised, namely
that penicillin is not effective in cases of, e.g. tuberculosis,
typhoid fever, poliomyelitis, and a number of other infectious
diseases. Consequently penicillin is not a universal remedy, but
it is of the highest value for certain diseases. And it appears
not improbable that, with the guidance of experience with
penicillin, it will be possible to produce new remedies which can
compete with or perhaps surpass it in certain respects.

Four years is a short time in which to arrive at definite
conclusions as to the value of a remedy. But during these last
few years experiences of penicillin have been assembled which,
under ordinary conditions, would have required decades. And
therefore there is no doubt at the present time that the
discovery of penicillin and its curative properties in the case
of various infection diseases for which this year's Nobel Prize
is awarded, is of the greatest importance for medical
science.

Sir Alexander Fleming, Doctor Chain, and
Sir Howard Florey. The story of penicillin is well-known
throughout the world. It affords a splendid example of different
scientific methods cooperating for a great common purpose. Once
again it has shown us the fundamental importance of basic
research. The starting-point was a purely academic investigation,
which led to a so-called accidental observation. This gave the
nucleus, around which one of the most efficient remedies ever
known could be crystallized. This difficult process was made
possible with the aid of modern biochemistry, bacteriology, and
clinical research. To overcome the numerous obstacles, all this
work demanded not only assistance from many different quarters,
but also an unusual amount of scientific enthusiasm, and a firm
belief in an idea. In a time when annihilation and destruction
through the inventions of man have been greater than ever before
in history, the introduction of penicillin is a brilliant
demonstration that human genius is just as well able to save life
and combat disease.

In the name of the Caroline Institute I extend to you hearty
congratulations on one of the most valuable contributions to
modern medicine. And now I have the honour of calling on you to
accept the Nobel Prize for Physiology or Medicine for the year
1945 from the hands of His Majesty the King.